Piperidine

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Piperidine

Piperidine is an organic compound

Organic compound

An organic compound is any member of a large class of chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of compounds such as carbonates, simple oxides of carbon and cyanides, as well as the allotropes of carbon, are considered Inorganic compound....
with the molecular formula (CH₂)₅NH. This heterocyclic

Heterocyclic compound

Heterocyclic compounds are organic compounds containing at least one atom of carbon, and at least one element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure....
amine

Amine

Amines are organic compounds and functional groups that contain a base nitrogen atom with a lone pair. Amines are derivative s of ammonia, wherein one or more hydrogen atoms are replaced by organic substituents such as alkyl and aryl groups....
consists of a six-membered ring containing five methylene

Methylene

Methylene is the chemical species, R2C:, named after methane, in which two of the carbon atom's valence electrons form no bonds. The word is applicable to:...
units and one nitrogen

Nitrogen

Nitrogen is a chemical element that has the symbol N and atomic number 7 and atomic mass 14.00674?. Elemental nitrogen is a colorless, odorless, tasteless and mostly inert diatomic gas at standard conditions, constituting 78% by volume of Earth's atmosphere....
atom. It is a colorless fuming liquid with an odor described as ammoniacal, pepper-like; the name comes from the genus name Piper
Piper (genus)

Piper, the pepper plants or pepper vines , are an economically and ecologically important genus in the family Piperaceae. It contains about 1,000-2,000 species of shrubs, herbs, and lianas, many of which are keystone species in their native habitat The diversification of this taxon is of interest to understanding the evolutio...
, which is the Latin word for pepper. Piperidine is a widely used building block and chemical reagent in the synthesis of organic compounds, including pharmaceuticals.

strially, piperidine is produced by the hydrogenation of pyridine

Pyridine

Pyridine is a simple and important heterocyclic aromatic organic compound with the formula CarbonHydrogenNitrogen. This colorless liquid with a distinctive fish-like odor is structurally related to benzene, wherein one CH group in the six-membered ring is replaced by a nitrogen atom....
, usually over a molybdenum

Molybdenum

Molybdenum , is a Group 6 element chemical element with the symbol Mo and atomic number 42. It has the List of elements by melting point melting point of any element....
sulfide catalyst:

C₅H₅N + 3 H₂ ? C₅H₁₀NH

Pyridine can also be reduced to piperidine by sodium in ethanol.

ridine itself has been obtained from pepper, from Psilocaulon absimile N.E.Br (Aizoaceae), and in Petrosimonia monandra.

The piperidine structural motif is present in numerous natural alkaloid

Alkaloid

Alkaloids are naturally occurring chemical compounds containing base nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base....
s.

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Encyclopedia

Piperidine is an organic compound

Organic compound

Heterocyclic compound

Amine

Methylene

Methylene is the chemical species, R2C:, named after methane, in which two of the carbon atom's valence electrons form no bonds. The word is applicable to:...
units and one nitrogen

Nitrogen

Production

Industrially, piperidine is produced by the hydrogenation of pyridine

Pyridine

Molybdenum

Molybdenum , is a Group 6 element chemical element with the symbol Mo and atomic number 42. It has the List of elements by melting point melting point of any element....
sulfide catalyst:

C₅H₅N + 3 H₂ ? C₅H₁₀NH

Pyridine can also be reduced to piperidine by sodium in ethanol.

Natural occurrence of piperidine and derivatives

Piperidine itself has been obtained from pepper, from Psilocaulon absimile N.E.Br (Aizoaceae), and in Petrosimonia monandra.

The piperidine structural motif is present in numerous natural alkaloid

Alkaloid

Alkaloids are naturally occurring chemical compounds containing base nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base....
s. These include piperine

Piperine

Piperine is the alkaloid responsible for the pungency of black pepper and long pepper, along with chavicine . It has also been used in some forms of traditional medicine and as an insecticide....
, which gives black pepper

Black pepper

Black pepper is a flowering plant vine in the family Piperaceae, cultivated for its fruit, which is usually dried and used as a spice and seasoning....
the hot taste. This gave the compound its name. Other examples are the fire ant

Fire ant

Fire ants, are stinging ants with over 280 species worldwide. They have several common names including Ginger Ants and Tropical Fire Ants , aka-kami-ari , and Feuerameise ....
toxin solenopsin

Solenopsin

Solenopsin is an alkaloid which inhibits angiogenesis via the phosphoinositol-3 kinase signaling pathway, in addition to contributing to the known and often despised toxic effect of fire ant venom....
, the nicotine

Nicotine

Nicotine is an alkaloid found in the nightshade family of plants which constitutes approximately 0.6?3.0% of dry weight of tobacco, with biosynthesis taking place in the roots, and accumulating in the leaves....
analog anabasine

Anabasine

Anabasine is a pyridine alkaloid found in the Tree Tobacco plant, a close relative of the common tobacco plant . It is similar to nicotine. Its principal industrial use is as an insecticide....
of the Tree Tobacco (Nicotiana glauca
Nicotiana glauca

Nicotiana glauca is sometimes referred to as Mustard Tree or Brazilian Tree Tobacco or simply Tree Tobacco. Its leaves are attached to the stalk by petioles , and its leaves and stems are neither wiktionary:pubescent nor sticky like Nicotiana tabacum....
), lobeline

Lobeline

Lobeline is a natural product alkaloid found in "Indian tobacco" , "Devil's tobacco" , "cardinal flower" , "great lobelia" , and Hippobroma longiflora....
of the indian tobacco, the toxic alkaloid coniine

Coniine

Coniine is a poisonous alkaloid found in Conium and the Sarracenia flava, and contributes to hemlock's fetid smell. It is a neurotoxin which disrupts the peripheral nervous system....
from poison hemlock, which was used to put Socrates to death.

Conformation

Piperidine prefers a chair conformation, similar to cyclohexane

Cyclohexane

Cyclohexane is a cycloalkane with the molecular formula Carbon6Hydrogen12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which are intermediates used in the production of nylon....
. Unlike cyclohexane, piperidine has two distinguishable chair conformations: one with the N–H bond in an axial position, and the other in an equatorial position. After much controversy during the 1950s–1970s, the equatorial conformation was found to be more stable by 0.72 kcal/mol in the gas phase. In nonpolar solvents, a range between 0.2 and 0.6 kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable. The two conformers interconvert rapidly through nitrogen inversion

Nitrogen inversion

In chemistry, a nitrogen compound like ammonia in a trigonal Pyramid geometry undergoes rapid nitrogen inversion whereby the molecule turns inside out....
; the free energy activation barrier for this process, estimated at 6.1 kcal/mol, is substantially lower than the 10.4 kcal/mol for ring inversion. In the case of N-methylpiperidine, the equatorial conformation is preferred by 3.16 kcal/mol, which is much larger than the preference in methylcyclohexane, 1.74 kcal/mol.


axial conformation	equatorial conformation

Reactions

Piperidine is a widely used secondary amine

Amine

Ketone

In organic chemistry, a ketone is a type of organic compound which contains a carbonyl group bonded to two other carbon atoms in the form:Neither of the substituents R1 and R2 may be equal to hydrogen ....
s to enamine

Enamine

An enamine is an saturation compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O....
s. Enamines derived from piperidine can be used in the Stork enamine alkylation

Stork enamine alkylation

Stork enamine alkylation, also known as the Stork-Enamine reaction, involves the addition of an enamine to an enone in a process similar to the Michael reaction ....
reaction.

Piperidine can be converted to the chloramine

Chloramine

Chloramine is a chemical compound with the chemical formula NH2Cl. It is usually used as a dilute solution where it is used as a disinfectant....
C₅H₁₀NCl with calcium hypochlorite

Calcium hypochlorite

Calcium hypochlorite is a chemical compound with chemical formula 2. It is widely used for water treatment and as a bleaching agent ....
. The resulting chloramine undergoes dehydrohalogenation

Dehydrohalogenation

Dehydrohalogenation is an organic chemistry reaction from which an alkene is obtained from an alkyl halide. It is also called the ?-Elimination reaction....
to afford the cyclic imine.

Uses

Piperidine is used as a solvent and as a base

Base (chemistry)

In chemistry, a base is most commonly thought of as an aqueous substance that can accept protons. A base is also often referred to as an alkali if OH- ions are involved....
. The same is true for certain derivatives: N-formylpiperidine

N-Formylpiperidine

N-Formylpiperidine is an organic compound with the formula C6H11NO. It is the amide of formic acid and piperidine. It can be used as a polar aprotic solvent, with better hydrocarbon solubility than other amide solvents such as dimethylformamide....
is a polar aprotic solvent with better hydrocarbon solubility than other amide solvents, and 2,2,6,6-tetramethylpiperidine

2,2,6,6-Tetramethylpiperidine

2,2,6,6-Tetramethylpiperidine or TMP or HTMP is a clear light yellow liquid with an amine odor. This amine is used in chemistry as a steric effects base because it can dissolve in organic solvents unlike ordinary bases such as potassium hydroxide....
is highly sterically hindered

Steric effects

Steric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and chemical reaction....
base, useful because of its low nucleophilicity and high solubility in organic solvents.

A significant industrial application of piperidine is for the production of dipiperidinyl dithiuram tetrasulfide, which is used as a rubber vulcanization

Vulcanization

Vulcanization refers to a specific curing process of rubber involving high heat and the addition of sulfur or other equivalent curatives. It is a chemical process in which polymer molecules are linked to other polymer molecules by atomic bridges composed of sulfur atoms or carbon to carbon bonds....
accelerator.

Otherwise piperidine and its derivatives are ubiquitous building blocks in the synthesis of pharmaceuticals and fine chemicals. The piperidine structure is e.g. found in the pharmaceuticals paroxetine

Paroxetine

Paroxetine is a selective serotonin reuptake inhibitor antidepressant. It was released in 1992 by the pharmaceutical company GlaxoSmithKline. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder and social phobia disorders in adult Patient#Outpatient vs inpatient....
, risperidone

Risperidone

Risperidone is an atypical antipsychotic developed by Janssen-Cilag....
, raloxifene

Raloxifene

Raloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast....
, minoxidil

Minoxidil

Minoxidil is a vasodilator medication known for its ability to slow or stop baldness and promote hair regrowth. It is available Over-the-counter drug for treatment of androgenic alopecia, among other baldness treatments, but measurable changes disappear within months after discontinuation of treatment....
, thioridazine

Thioridazine

Thioridazine is a piperidine antipsychotic psychoactive drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis....
, haloperidol

Haloperidol

Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacology similar to the phenothiazines....
, droperidol

Droperidol

Droperidol is an antidopaminergic medication used as an antiemetic and antipsychotic. Discovered at Janssen Pharmaceutica in 1961, it is a butyrophenone, and is a potent D2 antagonist with some histamine and serotonin antagonist activity....
, mesoridazine

Mesoridazine

Mesoridazine is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine....
, meperidine, melperone

Melperone

Melperone is a butyrophenone atypical antipsychotic. It is sold under the trade names Buronil, Burnil, and Eunerpan....
the psychochemical agents Ditran

Ditran

Ditran is an anticholinergic drug mixture, related to the chemical weapons 3-Quinuclidinyl benzilate .Ditran is composed of a mixture of 70% 1-ethyl- 2-pyrrolidinylmethyl- alpha- phenylcyclopentylglycolate and 30% 1-ethyl- 3-piperidyl- alpha- phenylcyclopentylglycolate....
-B (JB-329), N-methyl-3-piperidyl benzilate

N-Methyl-3-piperidyl benzilate

N-methyl-3-piperidyl benzilate is an anticholinergic drug related to the chemical weapons 3-Quinuclidinyl benzilate.N-methyl-3-piperidyl benzilate is less potent and shorter acting than 3-quinuclidyl benzilate, but like 3-QNB its effects on the central nervous system predominate over peripheral effects....
(JB-336) and in many others.

Piperidine is also commonly used in chemical degradation reactions, such as the sequencing of DNA in the cleavage of particular modified nucleotides. Piperidine is also commonly used as a base for the deprotection of Fmoc-amino acids used in solid-phase peptide synthesis

Peptide synthesis

In organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via peptide bonds which are also known as amide bonds....
.

Piperidine is listed as a Table II precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances

United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances

The 1988 United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances is one of three major drug control treaties currently in force....
due to its use (peaking in the 1970s) in the clandestine manufacture of PCP (also known as angel dust).